Artemisinin (Qinghaosu) and its analogs are the treatments of choice for cerebral or chloroquine resistant malaria or for patients with chloroquine allergy. Artemisinin is a naturally occurring substance, obtained by purification from sweet wormwood, Artemisia annua L. Artemisinin and its analogs are sesquiterpene lactones with a peroxide bridge, and are characterized by very low toxicity and poor water solubility. Artemisinin is known as a humoral immunosuppressive agent which is less active than cyclophosphamide, the latter being one of the major chemotherapeutic agents for carcinomas. Artemisinin stimulates cell-mediated immunity, and yet decreases abnormally elevated levels of polyamine regulatory proteins. It also markedly inhibits nucleic acid and protein syntheses. Further, it affects cellular membrane functions and decreases hepatic cytochrome oxidase enzyme system activity. Still further, it is virustatic against influenza and cidal against three groups of pathogenic parasites.
Known analogs of artemisinin which have higher solubility in water are dihydroartemisinin, artemether, artesunate, arteether, propylcarbonate dihydroartemisinin and artelinic acid. Dihydroartemisinin has an antimalarial potency which is 60% higher than that of artemisinin. Artemether and artesunate have antimalarial potencies which are 6 times and 5.2 times, respectively, that of artemisinin. In terms of their ability to inhibit nucleic acid synthesis, dihydroartemisinin, artemether, artesunate, arteether, and propylcarbonate dihydroartemisinin all have 100 times the activity of artemisinin, and protein synthesis is stimulated to an even greater extent by these compounds. Artesunate stimulates the immune system at low doses and inhibits it at high doses. Artelinic acid is the most water-soluble and the most stable of the group. Two of the compounds in this group have been demonstrated to display synergistic activity with doxorubicin (a chemotherapeutic agent) and miconazole (an antifungal agent) in the in vitro killing of Plasmodium falciparum, the etiologic agent of malaria.
The very low toxicity of these compounds to humans is a major benefit. Artesunate, for example, is twice as safe as artemether and only one-fiftieth as toxic as chloroquinine, the most common antimalarial. The first manifestation of toxicity of these compounds is generally a decreased reticulocyte count. Other manifestations include transient fever, decreased appetite and elevated blood transaminase levels, the latter an indication of hepatotoxicity.
U.S. Pat. No. 4,978,676 discloses the use of artemisinin and artemisinin analogs in the treatment of skin conditions such as psoriasis, blistering skin diseases, viral warts, and hemorrhoids.
U.S. Pat. No. 4,978,676 discloses the use of combinations artemisinin and artemisinin analogs with monocarboxylic acids, esters or amides in the treatment of papulosquamous skin diseases, including psoriasis, an eczematous skin diseases, including seborrheic and atopic dermatitis.
U.S. Pat. No. 5,219,880 discloses the use of artemisinin and artemisinin analogs in the treatment of warts, molluscum contagiosum and hemorrhoids.
U.S. Pat. No. 5,225,427 discloses certain 10-substituted ether derivatives of dihydroartemisinin alleged to exhibit antimalarial and antiprotozoal activity.
Artemisinin alone has been shown to be toxic to cancer cells in vitro at 20 to 180 .mu.M range (Sun et al., "Antitumor Activities of 4 Derivatives of Artemisic Acid and Artemisinin B in vitro," Chung-Kuo-Yao-Li-Hsueh-Pao 13:541-543 (1992)). The effect was found to be more effective for hepatoma and embryonic lung cells than against human gastric cancer cells. In another study (Woerdenbag et al., "Cytotoxicity of Artimisinin-related Endoperoxides to Erlich Ascites Tumor Cells," J. Nat. Prod. 56(6):849-856 (1993)), artemisinin was shown to have an IC.sub.50 value of 29.8 .mu.M on Ehrlich ascites tumor cells. Several derivatives of dihydroartemisinin (artemether, arteether, sodium artesunate, artelinic acid, and sodium artelinate) had IC.sub.50 values ranged from 12.2 to 19.9 .mu.M. A ether dimer of dihydroartemisinin was found to have an IC.sub.50 of 1.4 .mu.M. However, the toxicity of the dimer to normal cells was not tested. The authors of the latter paper concluded that, "The artemisinin-related endoperoxides showed cytotoxicity to Ehrlich ascites tumor cells at higher concentrations than those needed for in vitro antimalarial activity, as reported in the literature." However, serum concentrations at the levels reported by the two papers cannot be reached in vivo.
Artemisinin is a relatively safe drug with little side-effects even at high doses. Oral dose of 70 mg/kg/day for 6 days has been used in humans for malaria treatment. Furthermore, more potent analogs of this and similar compounds are also available. Higher efficacy of artemisinin action also can be achieved by other means. For example, artemisinin is more reactive with heme than free iron (Hong, et al. "The Interaction of Artemisinin with Malarial Hemozoin," Mol. Biochem. Parasit. 63:121-128 (1974)). Heme can be introduced into cells using transferrin (Stout, D. L., "The Role of Transferrin in Heme Transport," Biochim. Biophy. Res. Comm. 189:765-770 (1992)) or the heme-carrying compound hemoplexin (Smith et al., "Expression of Haemopexin-Transport System in Cultured Mouse Hepatoma Cells," Biochem. J. 256:941-950 (1988); Smith et al., "Hemopexin Joins Transferrin as Representative Members of a Distinct Class of Receptor-Mediated Endocytic Transport System," Europ. J. Cell Biol. 53:234-245 (1990)). The effectiveness of artemisinin also can be enhanced by increasing oxygen tension, decreasing intake of antioxidants, and blockade of peroxidase and catalase by drugs such as miconazole (Meshnick et al., "Activated Oxygen Mediates the Antimalarial Activity of Qinghaosu," Prog. Clin. Biol. Res. 313:95-104 (1989); Krungkrai et al., "The Antimalarial Action on Plasmodium falciparum of Qinghaosu and Artesunate in Combination with Agents Which Modulate Oxidant Stress," Tran. Roy. Soc. Trop. Med. Hyg. 81:710-714 (1989); Levander et al., "Qinghaosu, Dietary Vitamin E, Selenium, and Cod Liver Oil: Effect on the Susceptibility of Mice to the Malarial Parasite Plasmodium yoelii," Am. J. Clin. Ntr. 50:346-352 (1989)).
The endoperoxide moiety of artemisinin and its analogs has been found to be necessary for antimalarial activity, and analogs lacking this group have been found to be inactive. In the presence of heme, the endoperoxide bridge undergoes reductive decomposition to form a free radical and electrophilic intermediates. Accordingly, endoperoxide bearing compounds other than artemisinin and its analogs have been found to have antimalarial activity. For example, arteflene (Ro. 42-1611; Biirgen et al., "Ro. 42-1611, A New Effective Antimalarial: Chemical Structure and Biological Activity," Sixth International Congress for Infectious Diseases, Abst. 427, p. 152, April 1994, Prague), and the 1,2,4-trioxanes, such as the fenozans (Peters et al., "The Chemotherapy of Rodent Malaria. XLIX. The Activities of Some Synthetic 1,2,4-Trioxanes Against Chloroquinine-Sensitive and Chloroquinine-Resistant Parasites. Part 2: Structure-Activity Studies on cis-fused Cyclopenteno-1,2,4-Trioxane (Fenozans) Against Drug-Sensitive and Drug-Resistant Lines of Plasmodium berghei and P. yoelii spp. NS In Vivo," Annals of Tropical Medicine and Parasitology, 87(1):9-16 (1993)), and the 1,2,4,5-tetraoxanes (Vennerstrom et al., "Dispiro-1,2,4,5-tetraoxanes: A New Class of Antimalarial Peroxides," J. of Medicinal Chemistry, 35( 16):3023-3027 (1992)).